KR20060130744A - 피라졸로［３，４―ｂ］피리딘 화합물 및 이의 ｐｄｅ４억제제로서의 용도 - Google Patents
피라졸로［３，４―ｂ］피리딘 화합물 및 이의 ｐｄｅ４억제제로서의 용도 Download PDFInfo
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- KR20060130744A KR20060130744A KR1020067021438A KR20067021438A KR20060130744A KR 20060130744 A KR20060130744 A KR 20060130744A KR 1020067021438 A KR1020067021438 A KR 1020067021438A KR 20067021438 A KR20067021438 A KR 20067021438A KR 20060130744 A KR20060130744 A KR 20060130744A
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- compound
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- pharmaceutically acceptable
- ethyl
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| GB0405893.9 | 2004-03-16 | ||
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| GB0505214.7 | 2005-03-14 | ||
| GB0505214A GB0505214D0 (en) | 2005-03-14 | 2005-03-14 | Compounds |
Publications (1)
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|---|---|
| KR20060130744A true KR20060130744A (ko) | 2006-12-19 |
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| EP (2) | EP1735314A1 (enExample) |
| JP (2) | JP2007529464A (enExample) |
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| AR (1) | AR048175A1 (enExample) |
| AU (1) | AU2005223351A1 (enExample) |
| BR (1) | BRPI0508843A (enExample) |
| CA (1) | CA2559629A1 (enExample) |
| IL (1) | IL178011A0 (enExample) |
| MA (1) | MA28531B1 (enExample) |
| NO (1) | NO20064450L (enExample) |
| PE (1) | PE20060078A1 (enExample) |
| RU (1) | RU2378274C2 (enExample) |
| TW (1) | TW200602051A (enExample) |
| WO (2) | WO2005090354A1 (enExample) |
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| WO2005058892A1 (en) * | 2003-12-19 | 2005-06-30 | Glaxo Group Limited | Pyrazolo [3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors |
| CA2559629A1 (en) * | 2004-03-16 | 2005-09-29 | Glaxo Group Limited | Pyrazolo[3,4-b]pyridine compound, and its use as a pde4 inhibitor |
| EA200801997A1 (ru) | 2006-04-20 | 2009-04-28 | Глаксо Груп Лимитед | Новые соединения |
| TW200817006A (en) | 2006-06-23 | 2008-04-16 | Smithkline Beecham Corp | IL-8 receptor antagonist |
| JP2009545579A (ja) | 2006-08-01 | 2009-12-24 | グラクソ グループ リミテッド | ピラゾロ［３，４−ｂ］ピリジン化合物、及びｐｄｅ４阻害薬としてのその使用 |
| PE20081889A1 (es) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | Indol carboxamidas como inhibidores de ikk2 |
| CL2009000248A1 (es) | 2008-02-06 | 2009-09-11 | Glaxo Group Ltd | Compuestos derivados de pirazolo [3,4-b] piridin-5-il, inhibidores de la fosfodiesterasa de tipo iv (pde4) y antagonista de receptores muscarinicos de acetilcolina (machr); composicion farmaceutica que los comprende; y su uso en la preparacion de medicamentos utiles en el tratamiento de enferemedades respiratorias y alergicas |
| TW201000476A (en) | 2008-02-06 | 2010-01-01 | Glaxo Group Ltd | Dual pharmacophores-PDE4-muscarinic antagonistics |
| EP2249646A4 (en) * | 2008-02-06 | 2013-09-25 | Glaxo Group Ltd | PDE4 muscarinic Antagonist-DOPPELPHARMACOPHOREN |
| AR070563A1 (es) | 2008-02-06 | 2010-04-21 | Glaxo Group Ltd | Compuesto de un biciclo condensado pirazol-piridin-amina, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para el tratamiento de enfermedades respiratorias. |
| GB0806900D0 (en) * | 2008-04-16 | 2008-05-21 | Dow Corning | Fabric care emulsions |
| WO2009147187A1 (en) | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | 4-carboxamide indazole derivatives useful as inhibitors of p13-kinases |
| WO2010097248A1 (en) | 2009-01-13 | 2010-09-02 | Glaxo Group Limited | Pyrimidinecarboxamide derivatives as inhibitors of syk kinase |
| ES2542551T3 (es) | 2009-03-09 | 2015-08-06 | Glaxo Group Limited | 4-Oxadiazol-2-il-indazoles como inhibidores de PI3 cinasas |
| WO2010102968A1 (en) | 2009-03-10 | 2010-09-16 | Glaxo Group Limited | Indole derivatives as ikk2 inhibitors |
| WO2010106016A1 (en) | 2009-03-17 | 2010-09-23 | Glaxo Group Limited | Pyrimidine derivatives used as itk inhibitors |
| KR101642537B1 (ko) * | 2009-04-13 | 2016-07-25 | 술루르 수브라마니암 바난가무디 | 푸시드산나트륨을 사용하고 생체중합체를 혼입한 약용 푸시드산 크림 및 이의 제조 방법 |
| AU2010243613B2 (en) | 2009-04-30 | 2015-05-07 | Glaxo Group Limited | Oxazole substituted indazoles as PI3-kinase inhibitors |
| JP2013512880A (ja) | 2009-12-03 | 2013-04-18 | グラクソ グループ リミテッド | Ｐｉ３−キナーゼ阻害剤としてのインダゾール誘導体 |
| US20120238559A1 (en) | 2009-12-03 | 2012-09-20 | Glaxo Group Limited | Novel compounds |
| JP2013512879A (ja) | 2009-12-03 | 2013-04-18 | グラクソ グループ リミテッド | Ｐｉ３キナーゼの阻害剤としてのベンズピラゾール誘導体 |
| WO2011110575A1 (en) | 2010-03-11 | 2011-09-15 | Glaxo Group Limited | Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases |
| EP2613781B1 (en) | 2010-09-08 | 2016-08-24 | GlaxoSmithKline Intellectual Property Development Limited | Indazole derivatives for use in the treatment of influenza virus infection |
| PL2614058T3 (pl) | 2010-09-08 | 2015-12-31 | Glaxosmithkline Ip Dev Ltd | Polimorfy i sole n-[5-[4-(5-{[(2r,6s)-2,6-dimetylo-4-morfolinylo]-metylo}-1,3-oksazol-2-ilo)-1h-indazol-6-ilo]-2-(metyloksy)-3-pirydynylo]metanosulfonamidu |
| WO2012035055A1 (en) | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
| GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
| ES2610755T3 (es) | 2012-08-27 | 2017-05-03 | Aktiebolaget Electrolux | Sistema de posicionamiento de un robot |
| JP6198234B2 (ja) | 2013-04-15 | 2017-09-20 | アクティエボラゲット エレクトロラックス | 突出サイドブラシを備えたロボット真空掃除機 |
| CN110448222A (zh) | 2013-04-15 | 2019-11-15 | 伊莱克斯公司 | 机器人真空吸尘器 |
| US9011934B2 (en) | 2013-06-14 | 2015-04-21 | SatisPharma, LLC | Multi-purpose anti-itch treatment |
| AU2014336251A1 (en) | 2013-10-17 | 2016-04-14 | Glaxosmithkline Intellectual Property Development Limited | PI3K inhibitor for treatment of respiratory disease |
| CN105658218A (zh) | 2013-10-17 | 2016-06-08 | 葛兰素史克知识产权开发有限公司 | 用于治疗呼吸疾病的pi3k抑制剂 |
| WO2015090399A1 (en) | 2013-12-19 | 2015-06-25 | Aktiebolaget Electrolux | Robotic cleaning device and method for landmark recognition |
| JP6638988B2 (ja) | 2013-12-19 | 2020-02-05 | アクチエボラゲット エレクトロルックス | サイドブラシを有し、渦巻きパターンで動くロボットバキュームクリーナ |
| EP3084538B1 (en) | 2013-12-19 | 2017-11-01 | Aktiebolaget Electrolux | Robotic cleaning device with perimeter recording function |
| US9946263B2 (en) | 2013-12-19 | 2018-04-17 | Aktiebolaget Electrolux | Prioritizing cleaning areas |
| ES2675786T3 (es) | 2013-12-19 | 2018-07-12 | Aktiebolaget Electrolux | Control de velocidad adaptativo de cepillo lateral rotatorio |
| US10209080B2 (en) | 2013-12-19 | 2019-02-19 | Aktiebolaget Electrolux | Robotic cleaning device |
| US10149589B2 (en) | 2013-12-19 | 2018-12-11 | Aktiebolaget Electrolux | Sensing climb of obstacle of a robotic cleaning device |
| WO2015090439A1 (en) | 2013-12-20 | 2015-06-25 | Aktiebolaget Electrolux | Dust container |
| CN107072976A (zh) | 2014-05-12 | 2017-08-18 | 葛兰素史克知识产权第二有限公司 | 用于治疗传染性疾病的包含Danirixin的药物组合物 |
| US10518416B2 (en) | 2014-07-10 | 2019-12-31 | Aktiebolaget Electrolux | Method for detecting a measurement error in a robotic cleaning device |
| WO2016037636A1 (en) | 2014-09-08 | 2016-03-17 | Aktiebolaget Electrolux | Robotic vacuum cleaner |
| KR102271785B1 (ko) | 2014-09-08 | 2021-06-30 | 에이비 엘렉트로룩스 | 로봇 진공 청소기 |
| US9452178B1 (en) | 2014-10-22 | 2016-09-27 | SatisPharma, LLC | Acne formulations, treatments, and pressure sensitive patches for delivery of acne formulations |
| EP3230814B1 (en) | 2014-12-10 | 2021-02-17 | Aktiebolaget Electrolux | Using laser sensor for floor type detection |
| CN114668335A (zh) | 2014-12-12 | 2022-06-28 | 伊莱克斯公司 | 侧刷和机器人吸尘器 |
| KR102326401B1 (ko) | 2014-12-16 | 2021-11-16 | 에이비 엘렉트로룩스 | 로봇 청소 장치를 위한 청소 방법 |
| WO2016095965A2 (en) | 2014-12-16 | 2016-06-23 | Aktiebolaget Electrolux | Experience-based roadmap for a robotic cleaning device |
| KR102343513B1 (ko) | 2015-04-17 | 2021-12-28 | 에이비 엘렉트로룩스 | 로봇 청소 장치 및 로봇 청소 장치의 제어 방법 |
| KR102445064B1 (ko) | 2015-09-03 | 2022-09-19 | 에이비 엘렉트로룩스 | 로봇 청소 장치의 시스템 |
| SI3359541T1 (sl) * | 2015-10-09 | 2021-01-29 | Abbvie Overseas S.A R.L. | N-sulfonirani pirazolo(3,4 b)piridin-6-karboksamidi in postopki uporabe |
| GB201602527D0 (en) | 2016-02-12 | 2016-03-30 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| EP3430424B1 (en) | 2016-03-15 | 2021-07-21 | Aktiebolaget Electrolux | Robotic cleaning device and a method at the robotic cleaning device of performing cliff detection |
| CN109068908B (zh) | 2016-05-11 | 2021-05-11 | 伊莱克斯公司 | 机器人清洁设备 |
| EP3497100A1 (en) | 2016-08-08 | 2019-06-19 | GlaxoSmithKline Intellectual Property Development Limited | Chemical compounds |
| GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| JP7243967B2 (ja) | 2017-06-02 | 2023-03-22 | アクチエボラゲット エレクトロルックス | ロボット清掃デバイスの前方の表面のレベル差を検出する方法 |
| GB201712081D0 (en) | 2017-07-27 | 2017-09-13 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| KR20200058400A (ko) | 2017-09-26 | 2020-05-27 | 에이비 엘렉트로룩스 | 로봇 청소 장치의 이동 제어 |
| KR102034538B1 (ko) * | 2017-11-28 | 2019-10-21 | 주식회사한국파마 | Jak 저해제 화합물, 및 이의 제조방법 |
| CN111875594A (zh) * | 2020-07-21 | 2020-11-03 | 中国药科大学 | 具有磷酸二酯酶4b抑制活性的吲唑杂环类化合物 |
Family Cites Families (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE787249A (fr) * | 1971-08-05 | 1973-02-05 | Squibb & Sons Inc | Derives amino d'acides pyrazolopyridine carboxyliques, leurs esters et les sels de ces composes, ainsi que leurs procedes de preparation |
| US3833594A (en) * | 1971-08-05 | 1974-09-03 | Squibb & Sons Inc | Amino derivatives of pyrazolopyridine carboxylic acids and esters |
| US3856799A (en) * | 1971-08-05 | 1974-12-24 | Squibb & Sons Inc | Intermediates for production of amino derivatives of pyrazolopyridine carboxylic acids and esters |
| US3925388A (en) * | 1971-08-05 | 1975-12-09 | Squibb & Sons Inc | 4-Piperazino-{8 3,4-b{9 pyridine-5-carboxylic acids and esters |
| CA1003419A (en) | 1971-11-23 | 1977-01-11 | Theodor Denzel | Process for the production of pyrazolo (3,4-b) pyridines |
| US3979399A (en) * | 1972-11-15 | 1976-09-07 | E. R. Squibb & Sons, Inc. | Amino derivatives of pyrazolopyridine carboxamides |
| US3840546A (en) * | 1972-11-15 | 1974-10-08 | Squibb & Sons Inc | Amino derivatives of pyrazolopyridine carboxamides |
| US3833598A (en) | 1972-12-29 | 1974-09-03 | Squibb & Sons Inc | Amino derivatives of pyrazolopyridine-6-carboxylic acids and esters |
| US4115394A (en) | 1974-05-06 | 1978-09-19 | E. R. Squibb & Sons, Inc. | Amino derivatives of 6-phenylpyrazolo[3,4-b]pyridines |
| US4364948A (en) | 1981-09-28 | 1982-12-21 | Ici Americas Inc. | Pyrazolo[3,4-b]pyridine compounds |
| GB8425104D0 (en) * | 1984-10-04 | 1984-11-07 | Ici America Inc | Amide derivatives |
| US5547954A (en) * | 1994-05-26 | 1996-08-20 | Fmc Corporation | 2,4-Diamino-5,6-disubstituted-and 5,6,7-trisubstituted-5-deazapteridines as insecticides |
| US5593997A (en) * | 1995-05-23 | 1997-01-14 | Pfizer Inc. | 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors |
| US6326379B1 (en) * | 1998-09-16 | 2001-12-04 | Bristol-Myers Squibb Co. | Fused pyridine inhibitors of cGMP phosphodiesterase |
| RU2134498C1 (ru) * | 1998-12-08 | 1999-08-10 | Таран Александр Иванович | Контактный узел |
| IL148903A0 (en) | 1999-09-30 | 2002-09-12 | Neurogen Corp | Certain alkylene diamine-substituted heterocycles |
| GB9929685D0 (en) | 1999-12-15 | 2000-02-09 | Merck Sharp & Dohme | Therapeutic agents |
| JP2002020386A (ja) * | 2000-07-07 | 2002-01-23 | Ono Pharmaceut Co Ltd | ピラゾロピリジン誘導体 |
| US6670364B2 (en) * | 2001-01-31 | 2003-12-30 | Telik, Inc. | Antagonists of MCP-1 function and methods of use thereof |
| WO2002098878A1 (en) | 2001-02-08 | 2002-12-12 | Memory Pharmaceuticals Corporation | Trifluoromethylpurines as phosphodiesterase 4 inhibitors |
| TWI236474B (en) | 2001-04-03 | 2005-07-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
| US20050043319A1 (en) * | 2001-08-14 | 2005-02-24 | Exonhit Therapeutics Sa | Molecular target of neurotoxicity |
| FR2828693B1 (fr) * | 2001-08-14 | 2004-06-18 | Exonhit Therapeutics Sa | Nouvelle cible moleculaire de la neurotoxicite |
| EP1539753B1 (en) * | 2002-09-16 | 2009-09-09 | Glaxo Group Limited | Pyrazolo(3,4-b)pyridine compounds, and their use as phosphodiesterase inhibitors |
| GB0230045D0 (en) | 2002-12-23 | 2003-01-29 | Glaxo Group Ltd | Compounds |
| US7117650B2 (en) * | 2002-12-09 | 2006-10-10 | Forrest Dockery | Hanger system |
| WO2005058892A1 (en) | 2003-12-19 | 2005-06-30 | Glaxo Group Limited | Pyrazolo [3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors |
| GB0405937D0 (en) | 2004-03-16 | 2004-04-21 | Glaxo Group Ltd | Compounds |
| CA2559629A1 (en) * | 2004-03-16 | 2005-09-29 | Glaxo Group Limited | Pyrazolo[3,4-b]pyridine compound, and its use as a pde4 inhibitor |
| GB0405933D0 (en) | 2004-03-16 | 2004-04-21 | Glaxo Group Ltd | Compounds |
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2005
- 2005-03-15 CA CA002559629A patent/CA2559629A1/en not_active Abandoned
- 2005-03-15 BR BRPI0508843-7A patent/BRPI0508843A/pt not_active IP Right Cessation
- 2005-03-15 EP EP05716291A patent/EP1735314A1/en not_active Withdrawn
- 2005-03-15 JP JP2007503306A patent/JP2007529464A/ja active Pending
- 2005-03-15 US US10/598,973 patent/US20080275078A1/en not_active Abandoned
- 2005-03-15 WO PCT/GB2005/000987 patent/WO2005090354A1/en not_active Ceased
- 2005-03-15 US US10/598,838 patent/US7709497B2/en not_active Expired - Fee Related
- 2005-03-15 RU RU2006132684/04A patent/RU2378274C2/ru not_active IP Right Cessation
- 2005-03-15 KR KR1020067021438A patent/KR20060130744A/ko not_active Ceased
- 2005-03-15 EP EP05718039A patent/EP1740590A1/en not_active Withdrawn
- 2005-03-15 JP JP2007503404A patent/JP2007529486A/ja active Pending
- 2005-03-15 WO PCT/EP2005/003038 patent/WO2005090352A1/en not_active Ceased
- 2005-03-15 AU AU2005223351A patent/AU2005223351A1/en not_active Abandoned
- 2005-03-16 AR ARP050101028A patent/AR048175A1/es not_active Application Discontinuation
- 2005-03-16 TW TW094108054A patent/TW200602051A/zh unknown
- 2005-03-16 PE PE2005000299A patent/PE20060078A1/es not_active Application Discontinuation
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2006
- 2006-09-11 IL IL178011A patent/IL178011A0/en unknown
- 2006-10-02 NO NO20064450A patent/NO20064450L/no not_active Application Discontinuation
- 2006-10-13 MA MA29385A patent/MA28531B1/fr unknown
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|---|---|
| US20070280971A1 (en) | 2007-12-06 |
| RU2378274C2 (ru) | 2010-01-10 |
| EP1735314A1 (en) | 2006-12-27 |
| CA2559629A1 (en) | 2005-09-29 |
| TW200602051A (en) | 2006-01-16 |
| US20080275078A1 (en) | 2008-11-06 |
| WO2005090352A1 (en) | 2005-09-29 |
| AU2005223351A1 (en) | 2005-09-29 |
| JP2007529464A (ja) | 2007-10-25 |
| MA28531B1 (fr) | 2007-04-03 |
| IL178011A0 (en) | 2006-12-31 |
| NO20064450L (no) | 2006-11-14 |
| RU2006132684A (ru) | 2008-04-27 |
| AR048175A1 (es) | 2006-04-05 |
| BRPI0508843A (pt) | 2007-08-28 |
| JP2007529486A (ja) | 2007-10-25 |
| US7709497B2 (en) | 2010-05-04 |
| WO2005090354A1 (en) | 2005-09-29 |
| PE20060078A1 (es) | 2006-03-10 |
| EP1740590A1 (en) | 2007-01-10 |
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